Glucocorticosteroids are hydrophobic and have been provided in the form of aqueous suspensions. However, the aqueous suspension of a glucocorticosteroid compound have a problem that the contained steroid particles precipitate as time advances, and thus a patient needs to shake a container before use to disperse an active component homogeneously in the liquid phase. Even in case that a patient shook a container before use without fail, the particles in the suspension easily agglomerate to form cluster, thereby the particle diameter of the drug increases and the uniformity is lost. Such a ununiform dispersion caused a loss in an administration dose that is predetermined and consequent insufficient suppression of inflammation and pains.
In order to solve such a problem caused by the steroid, emulsion preparations have been proposed (Patent Literature 1, Non Patent Literatures 1, 2) as one of the methods. For example, Difluprednate O/W emulsion preparation (Durezol (Registered trademark): a 0.05% difluprednate preparation) has been confirmed to be stably applied to affected area with a uniform drug regardless of storage conditions or shaking before use.
However, the O/W emulsion preparation requires to use an oil solvent, which causes a problem of irritating effects such as uncomfortable sensations or congestion. Thus, it has been required to prepare glucocorticosteroid aqueous preparations without using oil solvent that can maintain the uniformity.
Modification of structure which gives hydrophilicity to the compound, such as Dexamethasone sodium phosphate, has been attempted to dissolve the compound in water. However, the water dissolved preparations could contain limited concentration of an active component due to the poor solubility.
As alternative aqueous solution containing a hardly soluble drug, nanosuspensions which contains nano-sized particles of an active component in an aqueous suspension have been proposed. It has been known that the particle diameter as small as nanometer substantially extends specific surface area in the nanosuspensions, and this enables faster maximization of the serum level of the component due to its increased solubility, variety of administration forms, and higher amount of an active component to be contained. As the nanosuspension of a glucocorticosteroid compound, it has been disclosed that the aqueous suspension containing fluticasone (D90 0.4 μm) and budesonide (D90 0.4 μm) produced by a wet mill using glass beads maintained the uniformity, crystal structure, and particle diameter after five weeks preservation at 4° C. (Non Patent Literature 3). Another approach for forming nanoparticles as bottom-up approach has been reported that precipitates hydrocortisone, a glucocorticosteroid compound, so as to generate nanoparticles having a mean diameter of about 300 nm, which is prepared as an aqueous suspension (Non Patent Literature 4). However, they also reported that the top-down approach (milling) is more advantageous in both intraocular pressure elevation and stability. Another nanosuspension containing a corticosteroid (specifically, mometasone furoate) mainly used for transnasal administration has been disclosed which contains corticosteroid having a D50 of 50 to 500 nm, a hydrophilic polymer, a wetting agent, and a complexing agent (Patent Literature 2). Additionally, an autoclave-sterilizable aqueous suspension of a glucocorticosteroid compound has been reported (Patent Literature 3).